Clinical Trial: Drug Study of Albuterol to Treat Acute Lung Injury

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo in Acute Lung Injury

Brief Summary: Acute Respiratory Distress Syndrome (ARDS) and a lesser condition that occurs prior to ARDS, Acute Lung Injury (ALI), are medical conditions that occur when there is severe inflammation and increased fluids (edema) in both lungs, making it hard for the lungs to function properly. Patients with these conditions require treatment that includes the use of a breathing machine (ventilator). The purpose of this study is to find out whether giving albuterol (a drug commonly used in asthmatics) or not giving albuterol to patients with ALI or ARDS makes a difference in how long it takes for a patient to be able to breath without the ventilator.

Detailed Summary:

Aerosolized beta-2 agonist therapy is anticipated to diminish the formation of lung edema, enhance clearance of lung edema and decrease pulmonary inflammation in patients with acute lung injury. Because beta-2 agonists have been shown to reduce permeability induced lung injury, it is anticipated that the severity of lung injury will be reduced by aerosolized beta-2 agonist therapy. The therapy may work by enhancing resolution of pulmonary edema by upregulating alveolar epithelial fluid transport mechanisms that will in turn enhance the clearance of alveolar edema. A reduction in the severity of lung injury and the quantity of alveolar edema should result in earlier extubation and more ventilator free days, improved pulmonary oxygen uptake, and improved lung compliance.

Study design: phase II/III prospective, randomized double-blind, placebo controlled trial.

  • In Phase II, patients will be treated with aerosolized albuterol 5.0 mg vs. normal saline (n=40-50)administered every 4 hours for 10 days following randomization or until 24 hours following extubation, whichever occurs first. The protocol stipulates that the 5.0 mg dose will be reduced to 2.5 mg if patients exceed defined heart rate limits.
  • In Phase III, the 5.0 mg dose will be used unless there is evidence that this dose has an unacceptable safety profile or dose reductions for tachycardia occur in a large fraction of patients. In that case, a lower dose of 2.5 mg will be used.
  • Patients will be followed for 90 days or until discharge from the hospital to home with unassisted breathing whichever occurs first.

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Current Primary Outcome: Number of Ventilator Free Days (VFD) [ Time Frame: Determined 28 days after a subject entered the study ]

Ventilator-free days (VFDs) is defined as the number of days from randomization to Day 28 after achieving unassisted breathing for patients who maintained unassisted breathing for at least two consecutive calendar days. If a patient achieved unassisted breathing, subsequently required additional assisted breathing, and once again achieved unassisted breathing, we counted only the VFDs after beginning the final period of unassisted breathing. Patients who died before Day 28 were assigned zero VFDs.


Original Primary Outcome:

  • Phase II: Number of adverse events and the proportion of participants who had study drug reduced in dosage and/or prematurely discontinued because of arrhythmia or other adverse events.
  • Phase III: Number of ventilator free days (VFD)


Current Secondary Outcome:

  • Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60 [ Time Frame: Determined 60 days after a subject entered the study ]
    Success for this efficacy variable was defined as being alive on study day 60 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those subjects alive in hospital at day 60 were considered to have survived.
  • Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90 [ Time Frame: Determined 90 days after a subject entered the study ]
    Success for this efficacy variable was defined as being alive on study day 90 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those participants who still remained in the hospital at 90 days after randomization were considered to have survived.
  • Number of ICU-free Days at 28 Days After Randomization [ Time Frame: Determined 28 days after a subject entered the study ]
    ICU (intensive care unit)-free days was defined as the number of days a subject was out of the ICU during study hospitalization from date of randomization up to study day 28. All incidences of ICU admission and discharge during the study hospitalization were captured. Any portion of a calendar day that a subject was in the ICU was counted as an ICU day.
  • Number of Organ Failure-free Days at Day 28 Following Randomization [ Time Frame: Daily from baseline to study day 28 ]
    Subjects were followed for development of organ failures from date of randomization to hospital discharge or study day 28, whichever was first. Organ failure was defined as present on any calendar day when the most abnormal vital signs or clinically available lab value met the definition of clinically significant organ failure according to the Brussels Organ Failure Table. Each day a patient was alive and free of a given clinically significant organ failure was scored as a failure-free day. The worst value for a calendar day was captured (lowest systolic BP, platelet count and highest creatinine and bilirubin values). Specific definitions of organ failure were: cardiovascular-systolic BP less than or equal to 90 mmHg or on a vasopressor; coagulation-platelet count less than or equal to 80 x 1000/mm3; Renal-creatinine less than or equal to 2.0 mg/dL; Hepatic-bilirubin less than or equal to 2.0 mg/dL.
  • Ventilator Free Days to Day 28 in the Subset of Participants With ARDS [ Time Frame: Determined 28 days after a subject entered the study ]
    Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200). P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2. VFD to Day 28 is defined as the number of days from the end of ventilation to day 28 in patients who maintained unassisted breathing for at least two consecutive calendar days. Patients who died before day 28 were assigned a VFD count of zero. If a patient returned to assisted breathing, subsequently required assisted breathing, and once again achieved unassisted breathing, only the VFDs after beginning the final period of unassisted breathing were counted. An increase in the number of VFDs was considered a positive result.
  • Hospital Mortality to Day 60 in the Subset of Participants With ARDS [ Time Frame: Determined 60 days after a subject entered the study ]
    Difference in the main outcome mortality to study day 60 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200) prior to randomization. P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2.
  • Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock [ Time Frame: Determined 28 days after a subject entered the study ]
    Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure<60 or the need for vasopressors (except dopamine <6 ug/kg/min).
  • Hospital Mortality up to Day 60 in Subjects With Baseline Shock [ Time Frame: Determined 60 days after a subject entered the study ]
    Difference in the main outcome hospital mortality to study day 60 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure<60 or the need for vasopressors (except dopamine <6 ug/kg/min).
  • Plasma Levels of IL-6 and IL-8 on Study Day 3 [ Time Frame: Measured at baseline and 3 days after randomization ]
    Biologic end-points were selected that would provide mechanistic insight into how albuterol improved lung function.

    Original Secondary Outcome:

    • Phase III: Mortality prior to hospital discharge with unassisted breathing (participants alive in hospital at Day 60 will be considered to have survived)
    • Mortality before hospital discharge home, with unassisted breathing, to Day 90 (participants alive in hospital at Day 90 will be considered to have survived)
    • Number of ICU-free days at Day 28 following study entry
    • Number of organ failure-free days at Day 28 following study entry (liver, kidney, heart, central nervous system, and hematologic) (Bernard, 1997).
    • Number of days between the day of first meeting criteria for weaning-readiness (protocol defined) and Day 28 following study entry
    • Mortality and VFDs in participants with pre-randomization PaO2/FIO2 less than or equal to 200
    • Change in plasma and mini-BAL levels of IL-6, IL-8, VWF, SPD, and total protein concentrations from baseline to Day 3
    • Ventilator free days and mortality prior to hospital discharge with unassisted breathing to day 60 and number of ventilator-free days to day 28 in patients with shock (protocol defined) at the time of study entry


    Information By: National Heart, Lung, and Blood Institute (NHLBI)

    Dates:
    Date Received: January 29, 2007
    Date Started: August 2007
    Date Completion:
    Last Updated: December 21, 2016
    Last Verified: December 2016